Thromb Haemost 2019; 119(04): 553-566
DOI: 10.1055/s-0039-1677803
Theme Issue Article
Georg Thieme Verlag KG Stuttgart · New York

Macrophage Migration Inhibitory Factor (MIF)-Based Therapeutic Concepts in Atherosclerosis and Inflammation

Dzmitry Sinitski*
1   Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München (KUM), Ludwig-Maximilians-University (LMU), Munich, Germany
,
Christos Kontos*
2   Division of Peptide Biochemistry, Technische Universität München (TUM), Freising, Germany
,
Christine Krammer*
1   Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München (KUM), Ludwig-Maximilians-University (LMU), Munich, Germany
,
Yaw Asare
3   Department of Translational Medicine, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München (KUM), Ludwig-Maximilians-University (LMU), Munich, Germany
,
Aphrodite Kapurniotu**
2   Division of Peptide Biochemistry, Technische Universität München (TUM), Freising, Germany
,
Jürgen Bernhagen**
1   Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München (KUM), Ludwig-Maximilians-University (LMU), Munich, Germany
4   Munich Heart Alliance, Munich, Germany
5   Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
› Author Affiliations
Funding This work was supported by Deutsche Forschungsgemeinschaft (DFG) grant SFB1123-A03 to J.B. and A.K., SFB1123-B03 to Y.A., by DFG within the framework of Munich Cluster for Systems Neurology (EXC 1010 SyNergy) and of LMUexc (LMU-Singapore strategic partnership) to J.B.
Further Information

Publication History

01 October 2018

21 December 2018

Publication Date:
04 February 2019 (online)

Abstract

Chemokines orchestrate leukocyte recruitment in atherosclerosis and their blockade is a promising anti-atherosclerotic strategy, but few chemokine-based approaches have advanced into clinical trials, in part owing to the complexity and redundancy of the chemokine network. Macrophage migration inhibitory factor (MIF) is a pivotal mediator of atherosclerotic lesion formation. It has been characterized as an inflammatory cytokine and atypical chemokine that promotes atherogenic leukocyte recruitment and lesional inflammation through interactions with the chemokine receptors CXCR2 and CXCR4, but also exhibits phase-specific CD74-mediated cardioprotective activity. The unique structural properties of MIF and its homologue MIF-2/D-DT offer intriguing therapeutic opportunities including small molecule-, antibody- and peptide-based approaches that may hold promise as inhibitors of atherosclerosis, while sparing tissue-protective classical chemokine pathways. In this review, we summarize the pros and cons of anti-MIF protein strategies and discuss their molecular characteristics and receptor specificities with a focus on cardiovascular disease.

* Contributed equally.


** Shared last authorship and correspondence.


 
  • References

  • 1 Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340 (02) 115-126
  • 2 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105 (09) 1135-1143
  • 3 Dahlöf B. Cardiovascular disease risk factors: epidemiology and risk assessment. Am J Cardiol 2010; 105 (1, Suppl): 3A-9A
  • 4 van der Vorst EP, Döring Y, Weber C. Chemokines and their receptors in atherosclerosis. J Mol Med (Berl) 2015; 93 (09) 963-971
  • 5 Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 2006; 354 (06) 610-621
  • 6 Bachelerie F, Ben-Baruch A, Burkhardt AM. , et al. International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol Rev 2013; 66 (01) 1-79
  • 7 Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 2011; 17 (11) 1410-1422
  • 8 Bäck M, Hansson GK. Anti-inflammatory therapies for atherosclerosis. Nat Rev Cardiol 2015; 12 (04) 199-211
  • 9 Ridker PM, Lüscher TF. Anti-inflammatory therapies for cardiovascular disease. Eur Heart J 2014; 35 (27) 1782-1791
  • 10 Ramji DP, Davies TS. Cytokines in atherosclerosis: key players in all stages of disease and promising therapeutic targets. Cytokine Growth Factor Rev 2015; 26 (06) 673-685
  • 11 Ruparelia N, Chai JT, Fisher EA, Choudhury RP. Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat Rev Cardiol 2017; 14 (03) 133-144
  • 12 Ridker PM, Everett BM, Thuren T. , et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377 (12) 1119-1131
  • 13 Bernhagen J, Calandra T, Mitchell RA. , et al. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 1993; 365 (6448): 756-759
  • 14 Bernhagen J, Krohn R, Lue H. , et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 2007; 13 (05) 587-596
  • 15 Calandra T, Roger T. Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 2003; 3 (10) 791-800
  • 16 Tillmann S, Bernhagen J, Noels H. Arrest functions of the MIF ligand/receptor axes in atherogenesis. Front Immunol 2013; 4: 115
  • 17 Burger-Kentischer A, Goebel H, Seiler R. , et al. Expression of MIF in different stages of human atherosclerosis. Circulation 2002; 105 (13) 1561-1566
  • 18 Zernecke A, Bernhagen J, Weber C. Macrophage migration inhibitory factor in cardiovascular disease. Circulation 2008; 117 (12) 1594-1602
  • 19 Tilstam PV, Qi D, Leng L, Young L, Bucala R. MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics. Expert Opin Ther Targets 2017; 21 (07) 671-683
  • 20 David JR. Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc Natl Acad Sci U S A 1966; 56 (01) 72-77
  • 21 Rich AR, Lewis MR. Migration of neutrophils and macrophages. Bull Johns Hopkins Hosp 1932; 50: 115-131
  • 22 Mischke R, Kleemann R, Brunner H, Bernhagen J. Cross-linking and mutational analysis of the oligomerization state of the cytokine macrophage migration inhibitory factor (MIF). FEBS Lett 1998; 427 (01) 85-90
  • 23 Sun HW, Bernhagen J, Bucala R, Lolis E. Crystal structure at 2.6-A resolution of human macrophage migration inhibitory factor. Proc Natl Acad Sci U S A 1996; 93 (11) 5191-5196
  • 24 Lolis E, Bucala R. Macrophage migration inhibitory factor. Expert Opin Ther Targets 2003; 7 (02) 153-164
  • 25 Flieger O, Engling A, Bucala R, Lue H, Nickel W, Bernhagen J. Regulated secretion of macrophage migration inhibitory factor is mediated by a non-classical pathway involving an ABC transporter. FEBS Lett 2003; 551 (1-3): 78-86
  • 26 Merk M, Baugh J, Zierow S. , et al. The Golgi-associated protein p115 mediates the secretion of macrophage migration inhibitory factor. J Immunol 2009; 182 (11) 6896-6906
  • 27 Hertelendy J, Reumuth G, Simons D. , et al. Macrophage migration inhibitory factor - a favorable marker in inflammatory diseases?. Curr Med Chem 2018; 25 (05) 601-605
  • 28 Morand EF, Leech M, Bernhagen J. MIF: a new cytokine link between rheumatoid arthritis and atherosclerosis. Nat Rev Drug Discov 2006; 5 (05) 399-410
  • 29 Morrison MC, Kleemann R. Role of macrophage migration inhibitory factor in obesity, insulin resistance, type 2 diabetes, and associated hepatic co-morbidities: a comprehensive review of human and rodent studies. Front Immunol 2015; 6: 308
  • 30 Sauler M, Bucala R, Lee PJ. Role of macrophage migration inhibitory factor in age-related lung disease. Am J Physiol Lung Cell Mol Physiol 2015; 309 (01) L1-L10
  • 31 O'Reilly C, Doroudian M, Mawhinney L, Donnelly SC. Targeting MIF in cancer: therapeutic strategies, current developments, and future opportunities. Med Res Rev 2016; 36 (03) 440-460
  • 32 Conroy H, Mawhinney L, Donnelly SC. Inflammation and cancer: macrophage migration inhibitory factor (MIF)--the potential missing link. QJM 2010; 103 (11) 831-836
  • 33 Chesney JA, Mitchell RA, Yaddanapudi K. Myeloid-derived suppressor cells-a new therapeutic target to overcome resistance to cancer immunotherapy. J Leukoc Biol 2017; 102 (03) 727-740
  • 34 Chesney JA, Mitchell RA. 25 years on: a retrospective on migration inhibitory factor in tumor angiogenesis. Mol Med 2015; 21 (Suppl. 01) S19-S24
  • 35 Wirtz TH, Tillmann S, Strüßmann T. , et al. Platelet-derived MIF: a novel platelet chemokine with distinct recruitment properties. Atherosclerosis 2015; 239 (01) 1-10
  • 36 Lin SG, Yu XY, Chen YX. , et al. De novo expression of macrophage migration inhibitory factor in atherogenesis in rabbits. Circ Res 2000; 87 (12) 1202-1208
  • 37 Burger-Kentischer A, Göbel H, Kleemann R. , et al. Reduction of the aortic inflammatory response in spontaneous atherosclerosis by blockade of macrophage migration inhibitory factor (MIF). Atherosclerosis 2006; 184 (01) 28-38
  • 38 Pan JH, Sukhova GK, Yang JT. , et al. Macrophage migration inhibitory factor deficiency impairs atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 2004; 109 (25) 3149-3153
  • 39 Amin MA, Haas CS, Zhu K. , et al. Migration inhibitory factor up-regulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 via Src, PI3 kinase, and NFkappaB. Blood 2006; 107 (06) 2252-2261
  • 40 Gregory JL, Morand EF, McKeown SJ. , et al. Macrophage migration inhibitory factor induces macrophage recruitment via CC chemokine ligand 2. J Immunol 2006; 177 (11) 8072-8079
  • 41 Atsumi T, Nishihira J, Makita Z, Koike T. Enhancement of oxidised low-density lipoprotein uptake by macrophages in response to macrophage migration inhibitory factor. Cytokine 2000; 12 (10) 1553-1556
  • 42 Kong YZ, Huang XR, Ouyang X. , et al. Evidence for vascular macrophage migration inhibitory factor in destabilization of human atherosclerotic plaques. Cardiovasc Res 2005; 65 (01) 272-282
  • 43 Calandra T, Bernhagen J, Metz CN. , et al. MIF as a glucocorticoid-induced modulator of cytokine production. Nature 1995; 377 (6544): 68-71
  • 44 Luo JY, Xu R, Li XM. , et al. MIF gene polymorphism rs755622 is associated with coronary artery disease and severity of coronary lesions in a Chinese Kazakh population: a case-control study. Medicine (Baltimore) 2016; 95 (04) e2617
  • 45 Herder C, Illig T, Baumert J. , et al. Macrophage migration inhibitory factor (MIF) and risk for coronary heart disease: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002. Atherosclerosis 2008; 200 (02) 380-388
  • 46 Ji K, Wang X, Li J. , et al. Macrophage migration inhibitory factor polymorphism is associated with susceptibility to inflammatory coronary heart disease. BioMed Res Int 2015; 2015: 315174
  • 47 Baugh JA, Chitnis S, Donnelly SC. , et al. A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis. Genes Immun 2002; 3 (03) 170-176
  • 48 Lan MY, Chang YY, Chen WH. , et al. Association between MIF gene polymorphisms and carotid artery atherosclerosis. Biochem Biophys Res Commun 2013; 435 (02) 319-322
  • 49 Müller II, Müller KA, Karathanos A. , et al. Impact of counterbalance between macrophage migration inhibitory factor and its inhibitor Gremlin-1 in patients with coronary artery disease. Atherosclerosis 2014; 237 (02) 426-432
  • 50 Müller II, Müller KAL, Schönleber H. , et al. Macrophage migration inhibitory factor is enhanced in acute coronary syndromes and is associated with the inflammatory response. PLoS One 2012; 7 (06) e38376
  • 51 Deng XN, Wang XY, Yu HY. , et al. Admission macrophage migration inhibitory factor predicts long-term prognosis in patients with ST-elevation myocardial infarction. Eur Heart J Qual Care Clin Outcomes 2018; 4 (03) 208-219
  • 52 Deng F, Zhao Q, Deng Y. , et al. Prognostic significance and dynamic change of plasma macrophage migration inhibitory factor in patients with acute ST-elevation myocardial infarction. Medicine (Baltimore) 2018; 97 (43) e12991
  • 53 Chan W, White DA, Wang XY. , et al. Macrophage migration inhibitory factor for the early prediction of infarct size. J Am Heart Assoc 2013; 2 (05) e000226
  • 54 Stoppe C, Rex S, Goetzenich A. , et al. Interaction of MIF family proteins in myocardial ischemia/reperfusion damage and their influence on clinical outcome of cardiac surgery patients. Antioxid Redox Signal 2015; 23 (11) 865-879
  • 55 Stoppe C, Werker T, Rossaint R. , et al. What is the significance of perioperative release of macrophage migration inhibitory factor in cardiac surgery?. Antioxid Redox Signal 2013; 19 (03) 231-239
  • 56 Stoppe C, Averdunk L, Goetzenich A. , et al. The protective role of macrophage migration inhibitory factor in acute kidney injury after cardiac surgery. Sci Transl Med 2018; 10 (441) eaan4886
  • 57 Luedike P, Hendgen-Cotta UB, Sobierajski J. , et al. Cardioprotection through S-nitros(yl)ation of macrophage migration inhibitory factor. Circulation 2012; 125 (15) 1880-1889
  • 58 Miller EJ, Li J, Leng L. , et al. Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature 2008; 451 (7178): 578-582
  • 59 Pohl J, Hendgen-Cotta UB, Rammos C. , et al. Targeted intracellular accumulation of macrophage migration inhibitory factor in the reperfused heart mediates cardioprotection. Thromb Haemost 2016; 115 (01) 200-212
  • 60 Qi D, Hu X, Wu X. , et al. Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion. J Clin Invest 2009; 119 (12) 3807-3816
  • 61 Rassaf T, Weber C, Bernhagen J. Macrophage migration inhibitory factor in myocardial ischaemia/reperfusion injury. Cardiovasc Res 2014; 102 (02) 321-328
  • 62 Koga K, Kenessey A, Powell SR, Sison CP, Miller EJ, Ojamaa K. Macrophage migration inhibitory factor provides cardioprotection during ischemia/reperfusion by reducing oxidative stress. Antioxid Redox Signal 2011; 14 (07) 1191-1202
  • 63 Qi D, Atsina K, Qu L. , et al. The vestigial enzyme D-dopachrome tautomerase protects the heart against ischemic injury. J Clin Invest 2014; 124 (08) 3540-3550
  • 64 Dayawansa NH, Gao X-M, White DA, Dart AM, Du XJ. Role of MIF in myocardial ischaemia and infarction: insight from recent clinical and experimental findings. Clin Sci (Lond) 2014; 127 (03) 149-161
  • 65 Leng L, Metz CN, Fang Y. , et al. MIF signal transduction initiated by binding to CD74. J Exp Med 2003; 197 (11) 1467-1476
  • 66 Ma H, Wang J, Thomas DP. , et al. Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the senescent heart. Circulation 2010; 122 (03) 282-292
  • 67 Schindler L, Dickerhof N, Hampton MB. , et al. Post-translational regulation of MIF: basis for functional fine-tuning. Redox Biol 2018; 15: 135-142
  • 68 Liehn EA, Kanzler I, Konschalla S. , et al. Compartmentalized protective and detrimental effects of endogenous MIF mediated by CXCR2 in a mouse model of myocardial ischemia/reperfusion. Arterioscler Thromb Vasc Biol 2013; 33 (09) 2180-2186
  • 69 Liehn EA, Tuchscheerer N, Kanzler I. , et al. Double-edged role of the CXCL12/CXCR4 axis in experimental myocardial infarction. J Am Coll Cardiol 2011; 58 (23) 2415-2423
  • 70 Alampour-Rajabi S, El Bounkari O, Rot A. , et al. MIF interacts with CXCR7 to promote receptor internalization, ERK1/2 and ZAP-70 signaling, and lymphocyte chemotaxis. FASEB J 2015; 29 (11) 4497-4511
  • 71 Chatterjee M, Borst O, Walker B. , et al. Macrophage migration inhibitory factor limits activation-induced apoptosis of platelets via CXCR7-dependent Akt signaling. Circ Res 2014; 115 (11) 939-949
  • 72 Tarnowski M, Grymula K, Liu R. , et al. Macrophage migration inhibitory factor is secreted by rhabdomyosarcoma cells, modulates tumor metastasis by binding to CXCR4 and CXCR7 receptors and inhibits recruitment of cancer-associated fibroblasts. Mol Cancer Res 2010; 8 (10) 1328-1343
  • 73 Cho Y, Crichlow GV, Vermeire JJ. , et al. Allosteric inhibition of MIF revealed by ibudilast. Proc Natl Acad Sci U S A 2010; 107 (25) 11313-11318
  • 74 Xu L, Li Y, Li D. , et al. Exploring the binding mechanisms of MIF to CXCR2 using theoretical approaches. Phys Chem Chem Phys 2015; 17 (05) 3370-3382
  • 75 Weber C, Kraemer S, Drechsler M. , et al. Structural determinants of MIF functions in CXCR2-mediated inflammatory and atherogenic leukocyte recruitment. Proc Natl Acad Sci U S A 2008; 105 (42) 16278-16283
  • 76 Kraemer S, Lue H, Zernecke A. , et al. MIF-chemokine receptor interactions in atherogenesis are dependent on an N-loop-based 2-site binding mechanism. FASEB J 2011; 25 (03) 894-906
  • 77 Klasen C, Ohl K, Sternkopf M. , et al. MIF promotes B cell chemotaxis through the receptors CXCR4 and CD74 and ZAP-70 signaling. J Immunol 2014; 192 (11) 5273-5284
  • 78 Schmitz C, Noels H, El Bounkari O. , et al. Mif-deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis. FASEB J 2018; 32 (08) 4428-4443
  • 79 Qin L, Kufareva I, Holden LG. , et al. Structural biology. Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine. Science 2015; 347 (6226): 1117-1122
  • 80 Wu B, Chien EY, Mol CD. , et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 2010; 330 (6007): 1066-1071
  • 81 Lacy M, Kontos C, Brandhofer M. , et al. Identification of an Arg-Leu-Arg tripeptide that contributes to the binding interface between the cytokine MIF and the chemokine receptor CXCR4. Sci Rep 2018; 8 (01) 5171
  • 82 Rajasekaran D, Gröning S, Schmitz C. , et al. Macrophage migration inhibitory factor-CXCR4 receptor interactions: evidence for partial allosteric agonism in comparison with CXCL12 chemokine. J Biol Chem 2016; 291 (30) 15881-15895
  • 83 Schwartz V, Lue H, Kraemer S. , et al. A functional heteromeric MIF receptor formed by CD74 and CXCR4. FEBS Lett 2009; 583 (17) 2749-2757
  • 84 Klasen C, Ziehm T, Huber M. , et al. LPS-mediated cell surface expression of CD74 promotes the proliferation of B cells in response to MIF. Cell Signal 2018; 46: 32-42
  • 85 Bertolino P, Rabourdin-Combe C. The MHC class II-associated invariant chain: a molecule with multiple roles in MHC class II biosynthesis and antigen presentation to CD4+ T cells. Crit Rev Immunol 1996; 16 (04) 359-379
  • 86 Merk M, Zierow S, Leng L. , et al. The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF). Proc Natl Acad Sci U S A 2011; 108 (34) E577 –E585
  • 87 Shi X, Leng L, Wang T. , et al. CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. Immunity 2006; 25 (04) 595-606
  • 88 Assis DN, Leng L, Du X. , et al. The role of macrophage migration inhibitory factor in autoimmune liver disease. Hepatology 2014; 59 (02) 580-591
  • 89 Monaco C, Nanchahal J, Taylor P, Feldmann M. Anti-TNF therapy: past, present and future. Int Immunol 2015; 27 (01) 55-62
  • 90 Loberg RD, Ying C, Craig M, Yan L, Snyder LA, Pienta KJ. CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. Neoplasia 2007; 9 (07) 556-562
  • 91 Loberg RD, Ying C, Craig M. , et al. Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Res 2007; 67 (19) 9417-9424
  • 92 Calandra T, Echtenacher B, Roy DL. , et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 2000; 6 (02) 164-170
  • 93 Kerschbaumer RJ, Rieger M, Völkel D. , et al. Neutralization of macrophage migration inhibitory factor (MIF) by fully human antibodies correlates with their specificity for the β-sheet structure of MIF. J Biol Chem 2012; 287 (10) 7446-7455
  • 94 Lan HY, Bacher M, Yang N. , et al. The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat. J Exp Med 1997; 185 (08) 1455-1465
  • 95 Bloom J, Sun S, Al-Abed Y. MIF, a controversial cytokine: a review of structural features, challenges, and opportunities for drug development. Expert Opin Ther Targets 2016; 20 (12) 1463-1475
  • 96 Zhang Y, Zeng X, Chen S. , et al. Characterization, epitope identification and mechanisms of the anti-septic capacity of monoclonal antibodies against macrophage migration inhibitory factor. Int Immunopharmacol 2011; 11 (09) 1333-1340
  • 97 Mahalingam D, Patel M, Sachdev J. , et al. Safety and efficacy analysis of imalumab, an anti-oxidized macrophage migration inhibitory factor (oxMIF) antibody, alone or in combination with 5-fluorouracil/leucovorin (5-FU/LV) or panitumumab, in patients with metastatic colorectal cancer (mCRC). Ann Oncol 2016; 2016: ii105
  • 98 Thiele M, Kerschbaumer RJ, Tam FW. , et al. Selective targeting of a disease-related conformational isoform of MIF ameliorates inflammatory conditions. J Immunol 2015; 195 (05) 2343-2352
  • 99 Schinagl A, Kerschbaumer RJ, Sabarth N. , et al. Role of the cysteine 81 residue of MIF as a molecular redox switch. Biochemistry 2018; 57 (09) 1523-1532
  • 100 Schinagl A, Thiele M, Douillard P. , et al. Oxidized MIF is a potential new tissue marker and drug target in cancer. Oncotarget 2016; 7 (45) 73486-73496
  • 101 Ochi A, Chen D, Schulte W. , et al. MIF-2/D-DT enhances proximal tubular cell regeneration through SLPI- and ATF4-dependent mechanisms. Am J Physiol Renal Physiol 2017; 313 (03) F767-F780
  • 102 Pohl J, Hendgen-Cotta UB, Stock P, Luedike P, Rassaf T. Elevated MIF-2 levels predict mortality in critically ill patients. J Crit Care 2017; 40: 52-57
  • 103 Merk M, Mitchell RA, Endres S, Bucala R. D-dopachrome tautomerase (D-DT or MIF-2): doubling the MIF cytokine family. Cytokine 2012; 59 (01) 10-17
  • 104 Benedek G, Meza-Romero R, Jordan K, Keenlyside L, Offner H, Vandenbark AA. HLA-DRα1-mMOG-35-55 treatment of experimental autoimmune encephalomyelitis reduces CNS inflammation, enhances M2 macrophage frequency, and promotes neuroprotection. J Neuroinflammation 2015; 12: 123
  • 105 Meza-Romero R, Benedek G, Yu X. , et al. HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis. J Immunol 2014; 192 (09) 4164-4173
  • 106 Vandenbark AA, Meza-Romero R, Benedek G. , et al. A novel regulatory pathway for autoimmune disease: binding of partial MHC class II constructs to monocytes reduces CD74 expression and induces both specific and bystander T-cell tolerance. J Autoimmun 2013; 40: 96-110
  • 107 Benedek G, Meza-Romero R, Andrew S. , et al. Partial MHC class II constructs inhibit MIF/CD74 binding and downstream effects. Eur J Immunol 2013; 43 (05) 1309-1321
  • 108 Berkova Z, Tao RH, Samaniego F. Milatuzumab - a promising new immunotherapeutic agent. Expert Opin Investig Drugs 2010; 19 (01) 141-149
  • 109 Borghese F, Clanchy FI. CD74: an emerging opportunity as a therapeutic target in cancer and autoimmune disease. Expert Opin Ther Targets 2011; 15 (03) 237-251
  • 110 Sun J, Hartvigsen K, Chou MY. , et al. Deficiency of antigen-presenting cell invariant chain reduces atherosclerosis in mice. Circulation 2010; 122 (08) 808-820
  • 111 Dolgin E. First GPCR-directed antibody passes approval milestone. Nat Rev Drug Discov 2018; 17 (07) 457-459
  • 112 Peng L, Damschroder MM, Cook KE, Wu H, Dall'Acqua WF. Molecular basis for the antagonistic activity of an anti-CXCR4 antibody. MAbs 2016; 8 (01) 163-175
  • 113 Jantunen E. Novel strategies for blood stem cell mobilization: special focus on plerixafor. Expert Opin Biol Ther 2011; 11 (09) 1241-1248
  • 114 Zernecke A, Bot I, Djalali-Talab Y. , et al. Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis. Circ Res 2008; 102 (02) 209-217
  • 115 Döring Y, Noels H, van der Vorst EPC. , et al. Vascular CXCR4 limits atherosclerosis by maintaining arterial integrity: evidence from mouse and human studies. Circulation 2017; 136 (04) 388-403
  • 116 Boisvert WA, Santiago R, Curtiss LK, Terkeltaub RA. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J Clin Invest 1998; 101 (02) 353-363
  • 117 Boisvert WA, Curtiss LK, Terkeltaub RA. Interleukin-8 and its receptor CXCR2 in atherosclerosis. Immunol Res 2000; 21 (2-3): 129-137
  • 118 Highfill SL, Cui Y, Giles AJ. , et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med 2014; 6 (237) 237ra67
  • 119 Stadtmann A, Zarbock A. CXCR2: from bench to bedside. Front Immunol 2012; 3: 263
  • 120 Joseph JP, Reyes E, Guzman J. , et al. CXCR2 inhibition - a novel approach to treating CoronAry heart DiseAse (CICADA): study protocol for a randomised controlled trial. Trials 2017; 18 (01) 473
  • 121 Kok T, Wasiel AA, Cool RH. , et al. Small-molecule inhibitors of MIF as an emerging class of therapeutics for immune disorders. Drug Discov Today 2018; 23 (11) 1910-1918
  • 122 Trivedi-Parmar V, Jorgensen WL. Advances and insights for small molecule inhibition of macrophage migration inhibitory factor. J Med Chem 2018; 61 (18) 8104-8119
  • 123 Ouertatani-Sakouhi H, El-Turk F, Fauvet B. , et al. Identification and characterization of novel classes of macrophage migration inhibitory factor (MIF) inhibitors with distinct mechanisms of action. J Biol Chem 2010; 285 (34) 26581-26598
  • 124 Bai F, Asojo OA, Cirillo P. , et al. A novel allosteric inhibitor of macrophage migration inhibitory factor (MIF). J Biol Chem 2012; 287 (36) 30653-30663
  • 125 Pantouris G, Bucala R, Lolis EJ. Structural plasticity in the C-terminal region of macrophage migration inhibitory factor-2 is associated with an induced fit mechanism for a selective inhibitor. Biochemistry 2018; 57 (26) 3599-3605
  • 126 Fingerle-Rowson G, Kaleswarapu DR, Schlander C. , et al. A tautomerase-null macrophage migration-inhibitory factor (MIF) gene knock-in mouse model reveals that protein interactions and not enzymatic activity mediate MIF-dependent growth regulation. Mol Cell Biol 2009; 29 (07) 1922-1932
  • 127 Pantouris G, Syed MA, Fan C. , et al. An analysis of MIF structural features that control functional activation of CD74. Chem Biol 2015; 22 (09) 1197-1205
  • 128 Cournia Z, Leng L, Gandavadi S. , et al. Discovery of human MIF-CD74 antagonists via virtual screening. J Med Chem 2009; 52 (02) 416-424
  • 129 Jorgensen WL, Gandavadi S, Du X. , et al. Receptor agonists of macrophage migration inhibitory factor. Bioorg Med Chem Lett 2010; 20 (23) 7033-7036
  • 130 Lubetsky JB, Dios A, Han J. , et al. The tautomerase active site of macrophage migration inhibitory factor is a potential target for discovery of novel anti-inflammatory agents. J Biol Chem 2002; 277 (28) 24976-24982
  • 131 Senter PD, Al-Abed Y, Metz CN. , et al. Inhibition of macrophage migration inhibitory factor (MIF) tautomerase and biological activities by acetaminophen metabolites. Proc Natl Acad Sci U S A 2002; 99 (01) 144-149
  • 132 Fox RJ, Coffey CS, Conwit R. , et al; NN102/SPRINT-MS Trial Investigators. Phase 2 trial of Ibudilast in progressive multiple sclerosis. N Engl J Med 2018; 379 (09) 846-855
  • 133 Brown KK, Blaikie FH, Smith RA. , et al. Direct modification of the proinflammatory cytokine macrophage migration inhibitory factor by dietary isothiocyanates. J Biol Chem 2009; 284 (47) 32425-32433
  • 134 Priego N, Zhu L, Monteiro C. , et al. STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis. Nat Med 2018; 24 (07) 1024-1035
  • 135 Heinrichs D, Berres M-L, Coeuru M. , et al. Protective role of MIF in nonalcoholic steatohepatitis. FASEB J 2014; 28 (12) 5136-5147
  • 136 Fosgerau K, Hoffmann T. Peptide therapeutics: current status and future directions. Drug Discov Today 2015; 20 (01) 122-128
  • 137 Lau JL, Dunn MK. Therapeutic peptides: historical perspectives, current development trends, and future directions. Bioorg Med Chem 2018; 26 (10) 2700-2707
  • 138 Henninot A, Collins JC, Nuss JM. The current state of peptide drug discovery: back to the future?. J Med Chem 2018; 61 (04) 1382-1414
  • 139 Zorzi A, Deyle K, Heinis C. Cyclic peptide therapeutics: past, present and future. Curr Opin Chem Biol 2017; 38: 24-29
  • 140 Leman LJ, Maryanoff BE, Ghadiri MR. Molecules that mimic apolipoprotein A-I: potential agents for treating atherosclerosis. J Med Chem 2014; 57 (06) 2169-2196
  • 141 Mallavia B, Recio C, Oguiza A. , et al. Peptide inhibitor of NF-κB translocation ameliorates experimental atherosclerosis. Am J Pathol 2013; 182 (05) 1910-1921
  • 142 Hong HY, Lee HY, Kwak W. , et al. Phage display selection of peptides that home to atherosclerotic plaques: IL-4 receptor as a candidate target in atherosclerosis. J Cell Mol Med 2008; 12 (5B): 2003-2014
  • 143 Koenen RR, von Hundelshausen P, Nesmelova IV. , et al. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat Med 2009; 15 (01) 97-103
  • 144 Koenen RR, Weber C. Therapeutic targeting of chemokine interactions in atherosclerosis. Nat Rev Drug Discov 2010; 9 (02) 141-153
  • 145 Figueiredo CR, Matsuo AL, Massaoka MH, Polonelli L, Travassos LR. Anti-tumor activities of peptides corresponding to conserved complementary determining regions from different immunoglobulins. Peptides 2014; 59: 14-19
  • 146 Figueiredo CR, Azevedo RA, Mousdell S. , et al. Blockade of MIF-CD74 signalling on macrophages and dendritic cells restores the antitumour immune response against metastatic melanoma. Front Immunol 2018; 9: 1132
  • 147 Yang L, Liu Z, Ren H. , et al. DRα1-MOG-35-55 treatment reduces lesion volumes and improves neurological deficits after traumatic brain injury. Metab Brain Dis 2017; 32 (05) 1395-1402
  • 148 Meza-Romero R, Benedek G, Leng L, Bucala R, Vandenbark AA. Predicted structure of MIF/CD74 and RTL1000/CD74 complexes. Metab Brain Dis 2016; 31 (02) 249-255
  • 149 Offner H, Sinha S, Burrows GG, Ferro AJ, Vandenbark AA. RTL therapy for multiple sclerosis: a Phase I clinical study. J Neuroimmunol 2011; 231 (1-2): 7-14
  • 150 Meza-Romero R, Benedek G, Jordan K. , et al. Modeling of both shared and distinct interactions between MIF and its homologue D-DT with their common receptor CD74. Cytokine 2016; 88: 62-70
  • 151 Crump MP, Gong JH, Loetscher P. , et al. Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. EMBO J 1997; 16 (23) 6996-7007
  • 152 Tamamura H, Hori A, Kanzaki N. , et al. T140 analogs as CXCR4 antagonists identified as anti-metastatic agents in the treatment of breast cancer. FEBS Lett 2003; 550 (1-3): 79-83
  • 153 DeMarco SJ, Henze H, Lederer A. , et al. Discovery of novel, highly potent and selective beta-hairpin mimetic CXCR4 inhibitors with excellent anti-HIV activity and pharmacokinetic profiles. Bioorg Med Chem 2006; 14 (24) 8396-8404
  • 154 Fujii N, Oishi S, Hiramatsu K. , et al. Molecular-size reduction of a potent CXCR4-chemokine antagonist using orthogonal combination of conformation- and sequence-based libraries. Angew Chem Int Ed Engl 2003; 42 (28) 3251-3253
  • 155 Ueda S, Oishi S, Wang ZX. , et al. Structure-activity relationships of cyclic peptide-based chemokine receptor CXCR4 antagonists: disclosing the importance of side-chain and backbone functionalities. J Med Chem 2007; 50 (02) 192-198
  • 156 Demmer O, Frank AO, Hagn F. , et al. A conformationally frozen peptoid boosts CXCR4 affinity and anti-HIV activity. Angew Chem Int Ed Engl 2012; 51 (32) 8110-8113
  • 157 Demmer O, Dijkgraaf I, Schumacher U. , et al. Design, synthesis, and functionalization of dimeric peptides targeting chemokine receptor CXCR4. J Med Chem 2011; 54 (21) 7648-7662
  • 158 Di Maro S, Trotta AM, Brancaccio D. , et al. Exploring the N-terminal region of C–X-C motif chemokine 12 (CXCL12): identification of plasma-stable cyclic peptides as novel, potent C–X-C chemokine receptor type 4 (CXCR4) antagonists. J Med Chem 2016; 59 (18) 8369-8380
  • 159 Di Maro S, Di Leva FS, Trotta AM. , et al. Structure-activity relationships and biological characterization of a novel, potent, and serum stable C–X-C chemokine receptor type 4 (CXCR4) antagonist. J Med Chem 2017; 60 (23) 9641-9652
  • 160 Groß A, Möbius K, Haußner C, Donhauser N, Schmidt B, Eichler J. Mimicking protein-protein interactions through peptide-peptide interactions: HIV-1 gp120 and CXCR4. Front Immunol 2013; 4: 257
  • 161 Möbius K, Dürr R, Haussner C, Dietrich U, Eichler J. A functionally selective synthetic mimic of the HIV-1 co-receptor CXCR4. Chemistry 2012; 18 (27) 8292-8295
  • 162 Wang J, Tong C, Yan X. , et al. Limiting cardiac ischemic injury by pharmacological augmentation of macrophage migration inhibitory factor-AMP-activated protein kinase signal transduction. Circulation 2013; 128 (03) 225-236
  • 163 Höllriegl W, Bauer A, Baumgartner B. , et al. Pharmacokinetics, disease-modifying activity, and safety of an experimental therapeutic targeting an immunological isoform of macrophage migration inhibitory factor, in rat glomerulonephritis. Eur J Pharmacol 2018; 820: 206-216
  • 164 Sparkes A, De Baetselier P, Brys L. , et al. Novel half-life extended anti-MIF nanobodies protect against endotoxic shock. FASEB J 2018; 32 (06) 3411-3422
  • 165 Kaufman JL, Niesvizky R, Stadtmauer EA. , et al. Phase I, multicentre, dose-escalation trial of monotherapy with milatuzumab (humanized anti-CD74 monoclonal antibody) in relapsed or refractory multiple myeloma. Br J Haematol 2013; 163 (04) 478-486
  • 166 Griffiths K, Dolezal O, Cao B. , et al. i-bodies, human single domain antibodies that antagonize chemokine receptor CXCR4. J Biol Chem 2016; 291 (24) 12641-12657
  • 167 Korkolopoulou P, Levidou G, El-Habr EA. , et al. Expression of interleukin-8 receptor CXCR2 and suppressor of cytokine signaling-3 in astrocytic tumors. Mol Med 2012; 18: 379-388
  • 168 Crichlow GV, Lubetsky JB, Leng L, Bucala R, Lolis EJ. Structural and kinetic analyses of macrophage migration inhibitory factor active site interactions. Biochemistry 2009; 48 (01) 132-139
  • 169 Rajasekaran D, Zierow S, Syed M, Bucala R, Bhandari V, Lolis EJ. Targeting distinct tautomerase sites of D-DT and MIF with a single molecule for inhibition of neutrophil lung recruitment. FASEB J 2014; 28 (11) 4961-4971
  • 170 Winner M, Meier J, Zierow S. , et al. A novel, MIF suicide substrate inhibits motility and growth of lung cancer cells. Cancer Res 2008; 68 (18) 7253-7257
  • 171 Al-Abed Y, Dabideen D, Aljabari B. , et al. ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis. J Biol Chem 2005; 280 (44) 36541-36544
  • 172 Tynan A, Mawhinney L, Armstrong ME. , et al. Macrophage migration inhibitory factor enhances Pseudomonas aeruginosa biofilm formation, potentially contributing to cystic fibrosis pathogenesis. FASEB J 2017; 31 (11) 5102-5110
  • 173 Mawhinney L, Armstrong ME, O' Reilly C. , et al. Macrophage migration inhibitory factor (MIF) enzymatic activity and lung cancer. Mol Med 2015; 20: 729-735
  • 174 Pease J, Horuk R. Chemokine receptor antagonists. J Med Chem 2012; 55 (22) 9363-9392
  • 175 Bizzarri C, Beccari AR, Bertini R, Cavicchia MR, Giorgini S, Allegretti M. ELR+ CXC chemokines and their receptors (CXC chemokine receptor 1 and CXC chemokine receptor 2) as new therapeutic targets. Pharmacol Ther 2006; 112 (01) 139-149
  • 176 Kleemann R, Hausser A, Geiger G. , et al. Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature 2000; 408 (6809): 211-216
  • 177 Nguyen MT, Beck J, Lue H. , et al. A 16-residue peptide fragment of macrophage migration inhibitory factor, MIF-(50-65), exhibits redox activity and has MIF-like biological functions. J Biol Chem 2003; 278 (36) 33654-33671
  • 178 Liang X. CXCR4, inhibitors and mechanisms of action. Chem Biol Drug Des 2008; 72 (02) 97-110
  • 179 Aboye TL, Ha H, Majumder S. , et al. Design of a novel cyclotide-based CXCR4 antagonist with anti-human immunodeficiency virus (HIV)-1 activity. J Med Chem 2012; 55 (23) 10729-10734